Self Tolerance Lecture 7 Lymphoid Organs in brief Primary lymphoid organs Bone marrow Thymus Secondary lymphoid organs Lymph nodes Spleen Mucosal-associated lymph Can you think of examples? Lymphoid Organs in brief High endothelial venule SLC chemokine Dendritic cell Stromal cell Follicular Dendritic cell 1 Lymphocyte Trafficking General Features of Immune Tolerance • Discriminate self vs. non-self • B and T lymphocytes Tregs • Simple: recognition of antigen • Self-tolerance: still many unknowns • Multiple Layers of Tolerance Central Tolerance Immature lymphocytes Peripheral Tolerance Mature lymphocytes • Tolerance IS NOT perfect! T Cell Maturation Pathway 2 T Cell Central Tolerance • T Cell Central Tolerance - Thymus • In this generative tissue, usually only self antigens are present Foreign antigens are presented in secondary lymphoid sites • Think back to T cell development: Rearrangement of T cell receptor genes Immature progenitors are resistant Express low level of TCR to apoptosis Low levels of FAS Double positive - CD4 & CD8 High levels of Bcl-2 (anti-apoptotic) Double-positive High levels of FAS Very low Bcl-2 Highly sensitive to apoptosis!!!! Thymic Selection • Positive Selection T lymphocyte Also called MHC restriction *** Cortical Epithelial Cells Recognition of self MHC MCH + antigen!! T cell receptor diversity All T cells will have receptors that recognize MHC + antigen Short lived • Negative Selection Thymic dendritic cells general self antigens Medullary epithelial cells tissue specific antigens Thymic Selection 1. TCRs must recognize MHC+self antigen to pass through positive selection. 2. TCRs must mediate negative selection - ie. Self tolerance. 3. Later, must also signal activation when faced with foreign peptides. HOW CAN THIS WORK? 1. Positive selection Relatively weak TCR/MCH+self antigen 2. Negative selection Strong TCR/ MCH+ self antigen 3. T cell activation Strong TCR / MCH + antigen from APC 3 T Cell Tolerance - Positive Selection See video - T Cell development Negative Selection Apoptosis Overview Apoptotic cell being engulfed 4 Two Distinct T Cell Pathways Programmed Cell Death Two distinct Pathways Signaling & activation of Caspases Intrinsic major pathway in all cells regulation of mito integrity release of key apoptotic factors Cytochrome C Extrinsic death receptors (Fas) trimeric cell surface proteins bind to specific ligands (FasL) pro-apoptotic - mito leakage T Cell Peripheral Tolerance Layering of Tolerance Induction 1. Central tolerance - thymus** 2. Traffic patterns 3. Secondary Lymph organs 4. Missing signal 5. Activation Peripheral Tolerance T cell receptors that recognize rare thymus antigens Too rare to have sufficient MCH/peptide complexes Functional Ignorance 5 T Cell Anergy Regulatory T Cells UNKNOWN Mechanism Occurs in the thymus as well - subset of CD4 cells Bypass negative selective and mature into Tregs This means that they have high affinity for self antigens Regulatory T Cells Marker for Tregs FOXp3 Different: have adhesion molecules 6 B Cell Tolerance - Mainly Central Self-Tolerance Summary 7 .